Clinical chemistry enables the analysis of biological fluids for diagnosing, monitoring, and/or treating the medical condition of a patient. By way of example, determining the level of analytes such as glucose, lactate, creatinine, electrolytes, and oxygen can be vitally important for monitoring and/or maintaining a patient's health and treatment. Moreover, a patient's reaction to the administration of certain substances (e.g. glucose) can be used in diagnostic stress-tests. Similarly, by monitoring the level of xenobiotics such as insulin or drugs and their metabolites, physicians can diagnose kidney and liver disorders or select appropriate dosing in drug treatment. For example, monitoring the pharmacokinetics of a drug under treatment conditions in a particular patient can allow individualized optimization of the treatment schedule and help avoid potentially serious drug-drug interactions.
Although centralized clinical laboratories can provide a wide array of assays for accurately determining the presence and/or concentration of various analytes, clinical laboratories typically require that a sample (e.g., blood) be obtained from a patient, shipped to a laboratory, and processed and tested prior to the results being communicated back to the patient's physician. While recent advances in point-of-care (POC) diagnostics have enabled some laboratory tests to be quickly performed at the patient's bedside, these assays are not without drawbacks as the accuracy and precision of POC instruments often suffer relative to their central lab counterparts.
By way of example, blood glucose has been the most frequently performed clinical chemistry laboratory test for the past several decades based, in part, on it serving as the primary indication for diabetes detection and monitoring of therapy. Over the last years, however, self-testing of blood glucose has become increasingly common with the advent of POC glucometers that allow an individual to lance their fingertip, expel a drop of blood onto a test strip that can be inserted into the glucometer, and obtain an almost immediate measurement of his or her blood glucose level.
Despite the frequency of sampling (e.g., at 15-, 30-, 60-, or 240-minute intervals as specified by protocols), monitoring provided by glucometers and other analyte monitors is nonetheless discontinuous, providing a snapshot of analyte levels in the blood at the moment that the sample was obtained. Accordingly, systems have been developed to continuously measure the concentration of analytes in subcutaneous interstitial fluid, for example, since the concentration of certain analytes (e.g., glucose) is highly correlated between these two fluid compartments (Bantle, et al., J. Lab. Clin. Med. 1997; 130: 436-441), incorporated herein by reference. By way of example, sensors for continuous monitoring of certain analytes (e.g., glucose) in interstitial fluid are known in the art. U.S. Pat. No. 6,579,690 of Bonnecaze et al. and U.S. Application Pub. No. 2008/0027296 of Hadvary et al., both of which are incorporated herein by reference, provide continuous analyte monitoring systems that may enable better glycemic control through continuous, real-time monitoring of a patient's interstitial fluid glucose levels. Some such systems, for example, employ an electrochemical sensor that can be implanted within subcutaneous tissue and remain in contact with the interstitial fluid for an extended time (e.g. several hours to a week or more). The voltage output of the sensor can be transmitted to a data processing unit (e.g. a microprocessor, a microcontroller, etc.) for converting the sensor output to a blood glucose equivalent value.
Like POC glucometers and other POC analyte measurement systems, implantable analyte monitoring systems can suffer from diminished accuracy and precision relative to their clinical laboratory counterparts. Moreover, the long-term implantation of these monitors can diminish the reliability of the data transmitted by the sensor(s) as other components in body fluids (e. g., proteins) can contaminate the sensors and cause inaccurate readings. As a result, current continuous analyte monitoring systems generally require frequent calibration or confirmation using other more invasive and/or less convenient techniques. By way of example, prior to treating a patient in whom their continuous blood glucose monitor indicates a low blood glucose level, a medical caretaker is generally required to confirm the levels using the standard-of-care POC glucometers. Likewise, diabetics using implantable, continuous glucose monitors are nonetheless prompted to provide a finger stick measurement for regular calibration of their monitors and/or prior to treatment. Accordingly, there remains a need for improved accuracy and reliability of implantable, continuous analyte monitoring systems, such as the continuous glucose monitor (CGM).
A CGM typically takes the form of a patch which is applied to the skin or implanted under the skin. Typically, the electrochemical sensor associated with the CGM patch is either implanted or inserted inside the human body and is therefore subject to a “foreign body response” where the body tries to render the sensor inert. This response changes the performance of the sensor as well as aging of the sensor may also change the performance. It is therefore desirable to have an in situ method for recalibrating sensors as their performance changes with time.
Systems, devices and methods for in situ calibration of implantable sensors are described in International Application No. PCT/US2012/070025 of Winkelman (published as WO 2013/090882 A1) incorporated herein by reference. In one aspect, Winkelman describes a system for monitoring the concentration of an analyte including a sensor configured to be implanted at an implant site in a patient's skin, the sensor configured to sense an analyte present in a biological fluid at the implant site. The described system can additionally include a reservoir, which contains a calibration fluid having a known concentration of the analyte, and a conduit for delivering the calibration fluid from the reservoir to the implant site, to allow for the calibration of the system.
While Winkelman provides the advantage of being an in situ calibration solution, it is limited by its single-point calibration methodology. With Winkelman, a “calibration fluid”, e.g. a control solution of a known value such as 100 mg/dL, is pumped from a reservoir into the interstitial tissue proximate to the sensor. The known value may be far from the value that the sensor was measuring, potentially causing a significant calibration error. Also, Winkelman only measures at a single point, such that both the gain and offset of the transfer function for the linear range of the sensor may be skewed. Still further, the method disclosed by Winkelman is limited in application due to the use of a single, fixed reservoir of calibration fluid.
These and other limitations of the prior art will become apparent to those of skill in the art upon a reading of the following descriptions and a study of the several figures of the drawing.